Programmed DNA Rearrangements During Differentiation: Immunoglobulin Class Switching

Citation

Davis, Mark Morris (1981) Programmed DNA Rearrangements During Differentiation: Immunoglobulin Class Switching. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/KFJS-G857. https://resolver.caltech.edu/CaltechETD:etd-04292005-082735

Abstract

The events of B-lymphocyte differentiation can be reconstructed in part through an analysis of the organization of heavy-chain genes isolated from B-cell tumors (myelomas). A mouse immunoglobulin alpha heavy-chain gene is shown to be composed of at least three non-contiguous segments of germline DNA -- a V_H gene segment, a J_H gene segment adjacent to the C_μ coding region, and a C_α gene segment. These gene segments are joined together by two distinct types of DNA rearrangements: variable region formation and immunoglobulin class switching. Three examples of IgM → IgA elass switching were examined and in each case a different site adjacent to C_μ and a different site adjacent to C_α were joined together in the process of switching. Two of the three C_μ sites shared significant homology to each other (15/25 nucleotides) and all three of C_α sites were highly homologous (22/30 nucleotides). We believe these sequences serve as recognition sites for class switching. Furthermore, the lack of homology between the C_α consensus sequence and sequences reported for C_γ1 and c_γ2b recombination sites suggests that this process is mediated by class-specific recognition sequences and, presumably, class-specific regulatory mechanisms. A number of predictions and possible explanations of immune phenomena result from this observation. Apparently nonproductive DNA rearrangements, occurring in the same tumor lines, seem also to utilize some of the _same regulatory apparati. In addition, it appears that in one example, MClOl, class switching has progressed from C_μ → C_α → C_γ1. This switching pathway presents difficulties for the simple deletional model of C_H switching.

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